Stimulant use such as cocaine has been shown to impact the human immune system. In regards to the human immunodeficiency virus (HIV) infection, a number of studies have indicated that cocaine users are at an increased risk for infection and display more rapid disease progression and morbidity. However due to many variables such as adherence to antiretroviral therapy, use of multiple classes of drugs and co-infections among others, it is difficult to fully appreciate the impact drug abuse has on HIV disease. In this proposal, we aim to develop an in vitro and in vivo system to examine the impact of cocaine on HIV infection. In Specific Aim #1, we propose to examine the effects of cocaine on quiescent CD4 T cell (G0) permissiveness to HIV and the kinetics of infection. This will be assessed by comparing the HIV infection kinetics of G0 cells in the presence or absence of cocaine (in vivo and in vitro). The mechanisms of cocaine effects will be determined by the use of neutralizing antibodies and receptor agonists and antagonists. In Specific Aim #2, we will investigate in vivo the effect of cocaine on HIV replication using the humanized BLT mouse model. These mice have a fully reconstituted human immune system that allows for the study of HIV infection. Mice will be infected with HIV prior or post-drug exposure and disease progression will be assessed compared to non-infected and/or untreated mice. In addition, we will examine the reactivation of viral reservoir from latently infected cells isolated from these mice. The proposed studies will expand our knowledge on HIV infection in quiescent cells in drug abusers, will shed light on the mechanisms which may activate provirus expression in this long-lived stable reservoir, and ultimately lead to the development of effective therapies tailored to individuals, both HIV seropositives and seronegatives, suffering from drug abuse.